Compositions for the treatment of diabetes and pre-diabetes

ABSTRACT

The invention relates to the compositions of formula I or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprises a salt of metformin and the methods for treating or preventing metabolic syndrome, prediabetes and diabetes may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of diabetes mellitus, obesity, lipid disorders, hypertriglyceridemia, hyperglycemia, hyperinsulinemia and insulin resistance.

PRIORITY

The present application claims the benefit of Indian Provisional PatentApplication No. 2448/CHE/2013 filed on 4 Jun. 2013; Indian ProvisionalPatent Application No. 5592/CHE/2013 filed on 4 Dec. 2013, IndianProvisional Patent Application No. 315/CHE/2014 filed on 25 Jan. 2014;Indian Provisional Patent Application No. 527/CHE/2014 filed on 5 Feb.2014; International Patent Application No. PCT/IB2013/059680 filed on 26Oct. 2013; International Patent Application No. PCT/IB2014/058634 filedon 29 Jan. 2014; International Patent Application No. PCT/IN2014/000089filed on 12 Feb. 2014, the entire disclosure of which is relied on forall purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION

This disclosure generally relates to compounds and compositions for thetreatment of diabetes and pre-diabetes. More particularly, thisinvention relates to treating subjects with a pharmaceuticallyacceptable dose of compounds, crystals, solvates, enantiomer,stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION

The multifaceted metabolic syndrome is defined as a number of majormetabolic disorders that enhances the risk of cardiovascular disease(CVD)—still the most important cause of death in the Western world—andtype 2 diabetes mellitus. It is also known as the insulin resistancesyndrome, syndrome X, dysmetabolic syndrome, or the deadly quartet, andis characterized by aberrations in a wide variety of metabolic riskmarkers such as hyperinsulinemia, impaired glucose metabolism, elevatedplasma levels of triglycerides, decreased levels of high-densitylipoprotein cholesterol (HDL-C), raised blood pressure, centrallydistributed obesity, impaired endothelial and haemostatic function, anda low-grade inflammatory state.

Type 2 Diabetes Mellitus (T2DM) is characterized by fasting andpostprandial hyperglycemia and relative insulin insufficiency. If leftuntreated, then hyperglycemia may cause long term microvascular andmacrovascular complications, such as nephropathy, neuropathy,retinopathy, and atherosclerosis. This disease causes significantmorbidity and mortality at considerable expense to patients, theirfamilies and society. The incidence of T2DM worldwide is now increasingat more rapid rates in Africa, Asia and South America than in Europe orthe U.S. Thus, T2DM is now considered worldwide epidemic.

Oxidative stress has long been associated with the late complications ofdiabetes, and has been implicated in their etiology. The reactive oxygenintermediates, produced in mitochondria, peroxisomes, and the cytosol,are scavenged by cellular defending systems, including enzymatic (ex.superoxide dismutase, glutathione peroxidase GPx, glutathione reductaseand catalase) and nonenzymatic antioxidants (ex. glutathione G-SH,thioredoxin, lipoic acid, ubiquinol, albumin, uric acid, flavonoids,vitamins A, C and E, etc.). Some are located in cell membranes, othersin the cytosol, and others in the blood plasma. In diabetes, an alteredoxidative metabolism is a consequence either of the chronic exposure tohyperglycaemia or of the absolute or relative insulin deficit; insulinregulates several reactions involved in oxido-reductive metabolism.Despite strong experimental evidence indicating that oxidative stressmay determine the onset and progression of late-diabetes complicationscontroversy exists about whether the increased oxidative stress ismerely associative rather than causal in diabetes.

Managing acute pathology of often relies on the addressing underlyingpathology and symptoms of the disease. There is currently a need in theart for new compositions to treatment or delay of the onset of diabetesand pre-diabetes and its associated complications progression.

SUMMARY OF THE INVENTION

The present invention provides compounds, compositions containing thesecompounds and methods for using the same to treat, prevent and/orameliorate the effects of the conditions such as diabetes andpre-diabetes.

The invention herein provides compositions comprising of formula I orpharmaceutical acceptable salts thereof. The invention also providespharmaceutical compositions comprising one or more compounds of formulaI or intermediates thereof and one or more of pharmaceuticallyacceptable carriers, vehicles or diluents. These compositions may beused in the treatment of diabetes and pre-diabetes and its associatedcomplications.

In certain embodiments, the present invention relates to the compoundsand compositions of formula I, or pharmaceutically acceptable saltsthereof,

with at least one polyunsaturated fatty acid molecular conjugate or aderivative of polyunsaturated fatty acid molecular conjugate representedby RH, or a mixture thereof

Wherein,

R¹, R², R³, R⁴ each independently represents H, D, CD₃ or CH₃;

RH independently represents

The compositions are typically compounds in the forms of salts ofbiguanide such as metformin and an omega-3 polyunsaturated fatty acidmolecular conjugate (RH) in which the biguanide moiety is protonated andthe acid moiety (RH) is at least in partially ionic form. In someinstances, however, for example depending on the pH of the environment,the composition may be in the form of a mixture of biguanide and acidcomponents. The invention also provides pharmaceutical compositionscomprising compositions of formula I and pharmaceutically acceptableexcipients.

In one embodiment as an example, the invention relates to a compound offormula I which is a salt of metformin and an omega-3 polyunsaturatedfatty acid molecular conjugate and is meant to include any polymorph,solvates and hydrates thereof.

RH in formula I is independently selected from

-   -   a molecular conjugate of eicosapentaenoic acid, D-pantothenic        acid and salsalate,    -   a molecular conjugate of eicosapentaenoic acid, D-pantothenic        acid and 2-((2-acetoxybenzoyl)oxy)benzoic acid,    -   a molecular conjugate of eicosapentaenoic acid, D-pantothenic        acid and nicotinic acid,    -   a molecular conjugate of eicosapentaenoic acid, D-pantothenic        acid and hydroxytyrosol,    -   a molecular conjugate of eicosapentaenoic acid, D-pantothenic        acid and R-lipoic acid,    -   a molecular conjugate of eicosapentaenoic acid and fumaric acid,        or    -   a molecular conjugate of eicosapentaenoic acid, D-pantothenic        acid.

The invention further provides methods for treating diabetes (especiallytype 2 diabetes), obesity, cardiac arrhythmia, myocardial infarction andelevated triglycerides. The compounds and compositions of this inventionmay provide high blood levels of the compositions of formula I, whenadministered to patients, preferably by oral administration.

Compounds of the present invention can be considered as designerdual-acting drugs and additionally possess a means for improving thebioavailability of their component moieties as a result of their highdegree of water solubility.

In certain embodiments, the invention relates to a mixture of metforminor a pharmaceutically acceptable salt thereof, (e.g., hydrochloride,succinate, fumarate) with an omega 3 polyunsaturated molecular conjugate(RH), or a pharmaceutically acceptable solvate, hydrate or polymorphsthereof. In one preferred embodiment, RH is a molecular conjugate ofeicosapentaenoic acid, D-pantothenic acid and salsalate, a molecularconjugate of eicosapentaenoic acid, D-pantothenic acid and2-((2-acetoxybenzoyl)oxy)benzoic acid or a molecular conjugate ofeicosapentaenoic acid, D-pantothenic acid and nicotinic acid.

Herein the application also provides a kit comprising any of thepharmaceutical compositions disclosed herein. The kit may compriseinstructions for use in the treatment of diabetes and pre-diabetes orits related complications.

The application also discloses a pharmaceutical composition comprising apharmaceutically acceptable carrier and any of the compositions herein.In some aspects, the pharmaceutical composition is formulated forsystemic administration, oral administration, sustained release,parenteral administration, injection, subdermal administration, ortransdermal administration.

Herein, the application additionally provides kits comprising thepharmaceutical compositions described herein. The kits may furthercomprise instructions for use in the treatment of diabetes andpre-diabetes or its related complications.

The compositions described herein have several uses. The presentapplication provides, for example, methods of treating a patientsuffering from diabetes and pre-diabetes or its related complicationsmanifested from metabolic or genetic conditions or disorders, metabolicdiseases, chronic diseases or disorders; neurodegenerative disorders,metabolic condition, Hepatology, Cancer, Respiratory, Hematological,Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocularcomplications.

In the illustrative embodiments, examples of compounds of formula I areas set forth below:

BRIEF DESCRIPTION OF DRAWINGS

FIG.-1: compound of Example-1, NMR (DMSO-d6) data.

FIG.-2 : compound of Example-2, NMR (DMSO-d6) data.

FIG.-3: compound of Example-3, NMR (DMSO-d6) data.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofordinary skill in the art.

The compounds of the present invention can be present in the form ofpharmaceutically acceptable biguanide salts. The compounds of thepresent invention can also be present in the form of pharmaceuticallyacceptable esters (i.e., the methyl and ethyl esters of the acids (RH)of formula I to be used as prodrugs). RH of formula I represents anomega-3 polyunsaturated fatty acid molecular conjugate in a prodrugform. The compounds of the present invention can also be solvated, i.e.hydrated. The solvation can be affected in the course of themanufacturing process or can take place i.e. as a consequence ofhygroscopic properties of an initially anhydrous compound of formula I(hydration).

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, lngold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

Pantothenic acid, also called pantothenate or vitamin B5 (a B vitamin),is a water-soluble vitamin. Only the dextrorotatory (D) isomer ofpantothenic acid possesses biologic activity. The levorotatory (L) formmay antagonize the effects of the dextrorotatory isomer. The systematicname: (R)-3-(2,4-Dihydroxy-3,3-dimethylbutanamido)propanoic acid.

As used herein, the term “metabolic condition” refers to an Inbornerrors of metabolism (or genetic metabolic conditions) are geneticdisorders that result from a defect in one or more metabolic pathways;specifically, the function of an enzyme is affected and is eitherdeficient or completely absent.

The term “polymorph” as used herein is art-recognized and refers to onecrystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, such as injections, and include withoutlimitation intravenous, intramuscular, intrapleural, intravascular,intrapericardial, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid,intraspinal and intrastemal injection and infusion.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofmammals, human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,solvent or encapsulating material involved in carrying or transportingany subject composition, from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of a subjectcomposition and not injurious to the patient. In certain embodiments, apharmaceutically acceptable carrier is non-pyrogenic. Some examples ofmaterials which may serve as pharmaceutically acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “predicting” as used herein refers to assessing the probabilityrelated diseases patient will suffer from abnormalities or complicationand/or terminal platelet aggregation or failure and/or death (i.e.mortality) within a defined time window (predictive window) in thefuture. The mortality may be caused by the central nervous system orcomplication. The predictive window is an interval in which the subjectwill develop one or more of the said complications according to thepredicted probability. The predictive window may be the entire remaininglifespan of the subject upon analysis by the method of the presentinvention.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected, suchas treating the metabolic syndrome and diabetes related disordersincludes such as diabetes, insulin resistance, hyperglycemia,pre-diabetes, neuropathic pain, liver disorders, neurological diseasessuch as alzheimers disease, parkinson's disease, huntington's disease,hepatitis, lipid disorders such as hypertriglyceridemia, arthritis,autoimmune diseases, pain, chronic pain, acute inflammation, chronicaneurysm, low hdl, lipid diseases, angina, atherosclerosis,cerebrovascular accident (stroke), cerebrovascular disease, congestiveheart failure, coronary artery disease, myocardial infarction (heartattack), peripheral vascular disease, aortic dissection, aorticstenosis, arrhythmia (irregular heartbeat), atrial fibrillation,cardiomyopathy, chest pain, claudication, congenital heart disease,congestive heart failure, deep vein thrombosis, edema, endocarditis,fainting, fitness: exercise for a healthy heart, heart attack, heartattack and atherosclerosis prevention, heart valve disease, vasculardisease, ventricular septal defect and other related diseases or anyother medical condition, is well understood in the art, and includesadministration of a composition which reduces the frequency of, ordelays the onset of, symptoms of a medical condition in a subjectrelative to a subject which does not receive the composition to asubject by administration of an agent even though such agent does nottreat the cause of the condition. The term “treating”, “treat” or“treatment” as used herein includes curative, preventative (e.g.,prophylactic), adjunct and palliative treatment.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

In certain embodiments, the pharmaceutical compositions described hereinare formulated in a manner such that said compositions will be deliveredto a patient in a therapeutically effective amount, as part of aprophylactic or therapeutic treatment. The desired amount of thecomposition to be administered to a patient will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the salts and compositions from the subject compositions. It isto be noted that dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions. Typically, dosing will be determined using techniquesknown to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular salt or composition may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

In certain embodiments, the dosage of the subject compositions providedherein may be determined by reference to the plasma concentrations ofthe therapeutic composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

When used with respect to a pharmaceutical composition or othermaterial, the term “sustained release” is art-recognized. For example, asubject composition which releases a substance over time may exhibitsustained release characteristics, in contrast to a bolus typeadministration in which the entire amount of the substance is madebiologically available at one time. For example, in particularembodiments, upon contact with body fluids including blood, spinalfluid, mucus secretions, lymph or the like, one or more of thepharmaceutically acceptable excipients may undergo gradual or delayeddegradation (e.g., through hydrolysis) with concomitant release of anymaterial incorporated therein, e.g., an therapeutic and/or biologicallyactive salt and/or composition, for a sustained or extended period (ascompared to the release from a bolus). This release may result inprolonged delivery of therapeutically effective amounts of any of thetherapeutic agents disclosed herein.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject composition,therapeutic or other material at a site remote from the disease beingtreated. Administration of an agent for the disease being treated, evenif the agent is subsequently distributed systemically, may be termed“local” or “topical” or “regional” administration, other than directlyinto the central nervous system, e.g., by subcutaneous administration,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

The present disclosure also contemplates prodrugs of the compositionsdisclosed herein, as well as pharmaceutically acceptable biguanide saltsof said prodrugs.

This application also discloses a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the composition of a compoundof Formula I may be formulated for systemic or topical or oraladministration. The pharmaceutical composition may be also formulatedfor oral administration, oral solution, injection, subdermaladministration, or transdermal administration. The pharmaceuticalcomposition may further comprise at least one of a pharmaceuticallyacceptable stabilizer, diluent, surfactant, filler, binder, andlubricant.

In many embodiments, the pharmaceutical compositions described hereinwill incorporate the disclosed compounds and compositions (Formula I) tobe delivered in an amount sufficient to deliver to a patient atherapeutically effective amount of a compound of formula I orcomposition as part of a prophylactic or therapeutic treatment. Thedesired concentration of formula I or its pharmaceutical acceptablesolvate, hydrate or polymorphs will depend on absorption, inactivation,and excretion rates of the drug as well as the delivery rate of thesalts and compositions from the subject compositions. It is to be notedthat dosage values may also vary with the severity of the condition tobe alleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions.Typically, dosing will be determined using techniques known to oneskilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular compound of formula I may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

The concentration and/or amount of any compound of formula I may bereadily identified by routine screening in animals, e.g., rats, byscreening a range of concentration and/or amounts of the material inquestion using appropriate assays. Known methods are also available toassay local tissue concentrations, diffusion rates of the salts orcompositions, and local blood flow before and after administration oftherapeutic formulations disclosed herein. One such method ismicrodialysis, as reviewed by T. E. Robinson et al., 1991, microdialysisin the neurosciences, Techniques, volume 7, Chapter 1. The methodsreviewed by Robinson may be applied, in brief, as follows. Amicrodialysis loop is placed in situ in a test animal. Dialysis fluid ispumped through the loop. When compounds with formula I such as thosedisclosed herein are injected adjacent to the loop, released drugs arecollected in the dialysate in proportion to their local tissueconcentrations. The progress of diffusion of the salts or compositionsmay be determined thereby with suitable calibration procedures usingknown concentrations of salts or compositions.

In certain embodiments, the dosage of the subject compounds of formula Iprovided herein may be determined by reference to the plasmaconcentrations of the therapeutic composition or other encapsulatedmaterials. For example, the maximum plasma concentration (Cmax) and thearea under the plasma concentration-time curve from time 0 to infinitymay be used.

Generally, in carrying out the methods detailed in this application, aneffective dosage for the compounds of Formulas I is in the range ofabout 0.01 mg/kg/day to about 100 mg/kg/day in single or divided doses,for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divideddoses. The compounds of Formulas I may be administered at a dose of, forexample, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day.Compounds of Formula I may also be administered to a human patient at adose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500,800, 1000, 2000, 5000 mg per day. In certain embodiments, thecompositions herein are administered at an amount that is less than 95%,90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound offormula I required for the same therapeutic benefit.

An effective amount of the compounds of formula I described hereinrefers to the amount of one of said salts or compositions which iscapable of inhibiting or preventing a disease.

An effective amount may be sufficient to prohibit, treat, alleviate,ameliorate, halt, restrain, slow or reverse the progression, or reducethe severity of a complication resulting from insulin resistance or type2 diabetes or dyslipidemia or lipid disorders and/or elevated reactiveoxidative-nitrosative species and/or abnormalities in glucose or lipidhomeostasis's, in patients who are at risk for such complications. Assuch, these methods include both medical therapeutic (acute) and/orprophylactic (prevention) administration as appropriate. The amount andtiming of compositions administered will, of course, be dependent on thesubject being treated, on the severity of the affliction, on the mannerof administration and on the judgment of the prescribing physician.Thus, because of patient-to-patient variability, the dosages given aboveare a guideline and the physician may titrate doses of the drug toachieve the treatment that the physician considers appropriate for thepatient. In considering the degree of treatment desired, the physicianmust balance a variety of factors such as age of the patient, presenceof preexisting disease, as well as presence of other diseases.

The compositions provided by this application may be administered to asubject in need of treatment by a variety of conventional routes ofadministration, including orally, topically, parenterally, e.g.,intravenously, subcutaneously or intramedullary. Further, thecompositions may be administered intranasally, as a rectal suppository,or using a “flash” formulation, i.e., allowing the medication todissolve in the mouth without the need to use water. Furthermore, thecompositions may be administered to a subject in need of treatment bycontrolled release dosage forms, site specific drug delivery,transdermal drug delivery, patch (active/passive) mediated drugdelivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination withpharmaceutically acceptable carriers, vehicles or diluents, in eithersingle or multiple doses. Suitable pharmaceutical carriers, vehicles anddiluents include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the compositions and the pharmaceutically acceptablecarriers, vehicles or diluents are then readily administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such asL-arginine, sodium citrate, calcium carbonate and calcium phosphate maybe employed along with various disintegrates such as starch, alginicacid and certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Appropriate materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof. Thecompounds of formula I may also comprise enterically coated comprisingof various excipients, as is well known in the pharmaceutical art.

For parenteral administration, solutions of the compositions may beprepared in (for example) sesame or peanut oil, aqueous propyleneglycol, or in sterile aqueous solutions may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media employed are all readily availableby standard techniques known to those skilled in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700,800 mg of the compounds of formula I disclosed herein, for instance,compounds of formula I or pharmaceutical acceptable salts of a compoundsof Formula I.

Generally, a composition as described herein may be administered orally,or parenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disorderthat prevent oral administration, or whenever the medication is bestapplied to the surface of a tissue or organ as determined by theattending physician. Localized administration may also be indicated, forexample, when a high dose is desired at the target tissue or organ. Forbuccal administration the active composition may take the form oftablets or lozenges formulated in a conventional manner.

The dosage administered will be dependent upon the identity of themetabolic syndrome, diabetes, insulin resistance, pre-diabetes, lipiddisorders or metabolic disease; the type of host involved, including itsage, health and weight; the kind of concurrent treatment, if any; thefrequency of treatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredientsare: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 toabout 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host bodyweight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, intravaginally,rectally, or ocularly in a concentration of from about 0.01 to about 50%w/w of the composition; preferably about 1 to about 20% w/w of thecomposition; and for parenteral use in a concentration of from about0.05 to about 50% w/v of the composition and preferably from about 5 toabout 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions ofsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient. For oral administrationeither solid or fluid unit dosage forms can be prepared.

As discussed above, the tablet core contains one or more hydrophilicpolymers. Suitable hydrophilic polymers include, but are not limited to,water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, gelling starches, swelling cross-linked polymers, and mixturesthereof. Examples of suitable water swellable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, andmixtures thereof. Examples of suitable polyalkylene glycols include, butare not limited to, polyethylene glycol. Examples of suitablethermoplastic polyalkylene oxides include, but are not limited to,poly(ethylene oxide). Examples of suitable acrylic polymers include, butare not limited to, potassium methacrylatedivinylbenzene copolymer,polymethylmethacrylate, high-molecular weight crosslinked acrylic acidhomopolymers and copolymers such as those commercially available fromNoveon Chemicals under the tradename CARBOPOL. Examples of suitablehydrocolloids include, but are not limited to, alginates, agar, guargum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gumarabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and mixtures thereof. Examples of suitable claysinclude, but are not limited to, smectites such as bentonite, kaolin,and laponite; magnesium trisilicate; magnesium aluminum silicate; andmixtures thereof. Examples of suitable gelling starches include, but arenot limited to, acid hydrolyzed starches, swelling starches such assodium starch glycolate and derivatives thereof, and mixtures thereof.Examples of suitable swelling cross-linked polymers include, but are notlimited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, andcross-linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable excipients for theformulation of tablets. Examples of suitable excipients include, but arenot limited to, fillers, adsorbents, binders, disintegrants, lubricants,glidants, release-modifying excipients, superdisintegrants,antioxidants, and mixtures thereof.

Suitable binders include, but are not limited to, dry binders such aspolyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders suchas water-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, andstarches; and mixtures thereof. Suitable disintegrants include, but arenot limited to, sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof. Suitable glidants include,but are not limited to, colloidal silicon dioxide. Suitablerelease-modifying excipients include, but are not limited to, insolubleedible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients include, but are not limited to, water-insoluble polymers andlow-melting hydrophobic materials, copolymers thereof, and mixturesthereof. Examples of suitable water-insoluble polymers include, but arenot limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers, copolymers thereof, and mixturesthereof. Suitable low-melting hydrophobic materials include, but are notlimited to, fats, fatty acid esters, phospholipids, waxes, and mixturesthereof. Examples of suitable fats include, but are not limited to,hydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil, free fatty acids and theirsalts, and mixtures thereof. Examples of suitable fatty acid estersinclude, but are not limited to, sucrose fatty acid esters, mono-, di-,and triglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoylmacrogol-32 glycerides, and mixtures thereof. Examples of suitablephospholipids include phosphotidyl choline, phosphotidyl serene,phosphotidyl enositol, phosphotidic acid, and mixtures thereof. Examplesof suitable waxes include, but are not limited to, carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate, andmixtures thereof. Examples of super disintegrants include, but are notlimited to, croscarmellose sodium, sodium starch glycolate andcross-linked povidone (crospovidone). In one embodiment the tablet corecontains up to about 5 percent by weight of such super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

In one embodiment, the immediate release coating has an averagethickness of at least 50 microns, such as from about 50 microns to about2500 microns; e.g., from about 250 microns to about 1000 microns. Inembodiment, the immediate release coating is typically compressed at adensity of more than about 0.9 g/cc, as measured by the weight andvolume of that specific layer.

In one embodiment, the immediate release coating contains a firstportion and a second portion, wherein at least one of the portionscontains the second pharmaceutically active agent. In one embodiment,the portions contact each other at a center axis of the tablet. In oneembodiment, the first portion includes the first pharmaceutically activeagent and the second portion includes the second pharmaceutically activeagent.

In one embodiment, the first portion contains the first pharmaceuticallyactive agent and the second portion contains the second pharmaceuticallyactive agent. In one embodiment, one of the portions contains a thirdpharmaceutically active agent. In one embodiment one of the portionscontains a second immediate release portion of the same pharmaceuticallyactive agent as that contained in the tablet core.

In one embodiment, the outer coating portion is prepared as a dry blendof materials prior to addition to the coated tablet core. In anotherembodiment the outer coating portion is included of a dried granulationincluding the pharmaceutically active agent.

Formulations with different drug release mechanisms described abovecould be combined in a final dosage form containing single or multipleunits. Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, or granules in a solid or liquid form.Typical, immediate release formulations include compressed tablets,gels, films, coatings, liquids and particles that can be encapsulated,for example, in a gelatin capsule. Many methods for preparing coatings,covering or incorporating drugs, are known in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, aplurality of drug-containing beads, granules or particles, or an outerlayer of a coated core dosage form, contains a therapeutically effectivequantity of the active agent with conventional pharmaceuticalexcipients. The immediate release dosage unit may or may not be coated,and may or may not be admixed with the delayed release dosage unit orunits (as in an encapsulated mixture of immediate releasedrug-containing granules, particles or beads and delayed releasedrug-containing granules or beads).

Extended release formulations are generally prepared as diffusion orosmotic systems, for example, as described in “Remington—The Science andPractice of Pharmacy”, 20th. Ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000). A diffusion system typically consists of one oftwo types of devices, reservoir and matrix, which are well known anddescribed in die art. The matrix devices are generally prepared bycompressing the drug with a slowly dissolving polymer carrier into atablet form.

An immediate release portion can be added to the extended release systemby means of either applying an immediate release layer on top of theextended release core; using coating or compression processes or in amultiple unit system such as a capsule containing extended and immediaterelease beads.

Delayed release dosage formulations are created by coating a soliddosage form with a film of a polymer which is insoluble in the acidenvironment of the stomach, but soluble in the neutral environment ofsmall intestines. The delayed release dosage units can be prepared, forexample, by coating a drug or a drug-containing composition with aselected coating material. The drug-containing composition may be atablet for incorporation into a capsule, a tablet for use as an innercore in a “coated core” dosage form, or a plurality of drug-containingbeads, particles or granules, for incorporation into either a tablet orcapsule.

A pulsed release dosage form is one that mimics a multiple dosingprofile without repeated dosing and typically allows at least a twofoldreduction in dosing frequency as compared to the drug presented as aconventional dosage form (e.g., as a solution or prompt drug-releasing,conventional solid dosage form). A pulsed release profile ischaracterized by a time period of no release (lag time) or reducedrelease followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of activeagent. In one embodiment of dosage forms that mimic a twice daily dosingprofile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60wt. %, of the total amount of active agent in the dosage form isreleased in the initial pulse, and, correspondingly approximately 70 wt.% to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount ofactive agent in the dosage form is released in the second pulse. Fordosage forms mimicking the twice daily dosing profile, the second pulseis preferably released approximately 3 hours to less than 14 hours, andmore preferably approximately 5 hours to 12 hours, followingadministration.

Another dosage form contains a compressed tablet or a capsule having adrug-containing immediate release dosage unit, a delayed release dosageunit and an optional second delayed release dosage unit. In this dosageform, the immediate release dosage unit contains a plurality of beads,granules particles that release drug substantially immediately followingoral administration to provide an initial dose. The delayed releasedosage unit contains a plurality of coated beads or granules, whichrelease drug approximately 3 hours to 14 hours following oraladministration to provide a second dose.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, may be prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of one or more compounds of formula I or other active agents areknown, or will be apparent in light of this disclosure, to those skilledin this art. For examples of methods of preparing pharmaceuticalcompositions, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 19th Edition (1995).

In addition, in certain embodiments, subject compositions of the presentapplication maybe lyophilized or subjected to another appropriate dryingtechnique such as spray drying. The subject compositions may beadministered once, or may be divided into a number of smaller doses tobe administered at varying intervals of time, depending in part on therelease rate of the compositions and the desired dosage.

Formulations useful in the methods provided herein include thosesuitable for oral, nasal, topical (including buccal and sublingual),rectal, vaginal, aerosol and/or parenteral administration. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any methods well known in the art of pharmacy. The amountof a subject composition which may be combined with a carrier materialto produce a single dose may vary depending upon the subject beingtreated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the stepof bringing into association subject compositions with the carrier and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a subject composition with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

The compounds of formula I described herein may be administered ininhalant or aerosol formulations. The inhalant or aerosol formulationsmay comprise one or more agents, such as adjuvants, diagnostic agents,imaging agents, or therapeutic agents useful in inhalation therapy. Thefinal aerosol formulation may for example contain 0.005-90% w/w, forinstance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers and/or anyof the following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, acetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using lactose or milk sugars, as wellas high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject compositions, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, corn, peanut, sunflower,soybean, olive, castor, and sesame oils), glycerol, tetrahydrofurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the subject compositions, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol, and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax, or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the appropriate body cavity and release theencapsulated compound(s) and composition(s). Formulations which aresuitable for vaginal administration also include pessaries, tampons,creams, gels, pastes, foams, or spray formulations containing suchcarriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches, andinhalants. A subject composition may be mixed under sterile conditionswith a pharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required. For transdermaladministration, the complexes may include lipophilic and hydrophilicgroups to achieve the desired water solubility and transport properties.

The ointments, pastes, creams and gels may contain, in addition tosubject compositions, other carriers, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Powders and sprays may contain, in additionto a subject composition, excipients such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicates and polyamide powder, ormixtures of such substances. Sprays may additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

Methods of delivering a composition or compositions via a transdermalpatch are known in the art. Exemplary patches and methods of patchdelivery are described in U.S. Pat. Nos. 6,974,588, 6,564,093,6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

In another embodiment, a transdermal patch may comprise: a substratesheet comprising a composite film formed of a resin compositioncomprising 100 parts by weight of a polyvinyl chloride-polyurethanecomposite and 2-10 parts by weight of astyrene-ethylene-butylene-styrene copolymer, a first adhesive layer onthe one side of the composite film, and a polyalkylene terephthalatefilm adhered to the one side of the composite film by means of the firstadhesive layer, a primer layer which comprises a saturated polyesterresin and is formed on the surface of the polyalkylene terephthalatefilm; and a second adhesive layer comprising a styrene-diene-styreneblock copolymer containing a pharmaceutical agent layered on the primerlayer. A method for the manufacture of the above-mentioned substratesheet comprises preparing the above resin composition molding the resincomposition into a composite film by a calendar process, and thenadhering a polyalkylene terephthalate film on one side of the compositefilm by means of an adhesive layer thereby forming the substrate sheet,and forming a primer layer comprising a saturated polyester resin on theouter surface of the polyalkylene terephthalate film.

Another type of patch comprises incorporating the drug directly in apharmaceutically acceptable adhesive and laminating the drug-containingadhesive onto a suitable backing member, e.g. a polyester backingmembrane. The drug should be present at a concentration which will notaffect the adhesive properties, and at the same time deliver therequired clinical dose.

Transdermal patches may be passive or active. Passive transdermal drugdelivery systems currently available, such as the nicotine, estrogen andnitroglycerine patches, deliver small-molecule drugs. Many of the newlydeveloped proteins and peptide drugs are too large to be deliveredthrough passive transdermal patches and may be delivered usingtechnology such as electrical assist (iontophoresis) for large-moleculedrugs.

Iontophoresis is a technique employed for enhancing the flux of ionizedsubstances through membranes by application of electric current. Oneexample of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646to Theeuwes. The principal mechanisms by which iontophoresis enhancesmolecular transport across the skin are (a) repelling a charged ion froman electrode of the same charge, (b) electroosmosis, the convectivemovement of solvent that occurs through a charged pore in response thepreferential passage of counter-ions when an electric field is appliedor (c) increase skin permeability due to application of electricalcurrent.

In some cases, it may be desirable to administer in the form of a kit,it may comprise a container for containing the separate compositionssuch as a divided bottle or a divided foil packet. Typically the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a plastic material that may betransparent.

Methods and compositions for the treatment of diabetes and pre-diabetes.Among other things, herein is provided a method of treating diabetes andpre-diabetes, comprising administering to a patient in need thereof atherapeutically effective amount of compound of Formula I:

with at least one polyunsaturated fatty acid molecular conjugate or aderivative of polyunsaturated fatty acid molecular conjugate representedby RH, or a mixture thereof

Wherein,

R¹, R², R³, R⁴ each independently represents H, D, CD₃ or CH₃;

RH independently represents

Methods of Making

The present invention is exemplified by the following non-limitingexamples. Examples of synthetic pathways useful for making compounds offormula I are set forth in example below and generalized in example-1,example-2 and example-3:

Example-1

Synthesis of Compound-3:

A solution of (D)-(−)-pantolactone (25.0 g, 192.30 mmol), β-alaninetert-butyl ester HCl (25.0 g, 137.66 mmol) and Et₃N (22.0 mL, 168.0mmol) in dioxane (250 mL) was heated at 65° C. for 3 days. The reactionmixture was cooled to RT, filtered the salt, filtrate was evaporated invacuo and purified by column chromatography to afford compound 3 (32.0g, 116.0 mmol) as light yellow syrup. Rf: 0.3 (80% EtOAc/Hexane); LCMS(M+H): 276.2; Yield: 84.5%.

Synthesis of Compound-5:

To a stirred solution of eicosapentaenoic acid (40.0 g, 132.45 mmol) andDIPEA (20 mL, 108.5 mmol) in THF (250 mL) was added CDI (21.5 g, 132.45mmol) in portions at below 10° C. over a period of 15 min. Afterstirring for 1 h at RT, was added compound 3 (36.0 G, 130.9 mmol) in THF(200 mL) and cat amount of DMAP and resulting mixture was stirred at RTfor 3 days. The solvent was evaporated in vacuo and the crude materialwas subjected to column chromatography (30-50% EtOAc/Hexanes, Rf: 0.4)to afford compound 5 (27.0 g, 48.3 mmol) as yellow oil. LCMS (M+H):560.8; Yield: 36.5%.

Synthesis of Compound-6:

To a solution of compound 5 (10 g, 17.9 mmol) in CH₂Cl₂ (160 mL) wasadded trifluoroacetic acid (10 mL) and the mixture was stirred for 2days at RT. The Solvent was evaporated in vacuo and the crude materialwas purified by column chromatography (50-70% EtOAc/Hexanes, Rf: 0.25)to afford Compound 6 (4.6 g, 9.1 mmol) as yellow oil. Yield: 51%; LCMS(M+H): 504.5.

Preparation of amino(3,3-dimethylguanidino)methaniminium3-((R)-2-hydroxy-4-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyloxy)-3,3-dimethylbutanamido)propanoate

Compound 6 (4.0 g, 7.9 mmol) and metformin free base (1.0 g, 7.7 mmol)were mixed in CH₂Cl₂ (50 mL) and stirred at RT for 1 h. The solvent wasevaporated to give syrup, which was triturated with ether (100 mL) andstirred for 2 h at RT. The residual mixture was filtered and washed withether (2×20 mL) and dried for 6 hrs in a vacuum oven resulting (3.3 g,5.2 mmol) as a yellow solid. Yield: 66%. Molecular Formula: C₃₃H₅₆N₆O₆;Molecular Wt: 632.83.

Example-2

Synthesis of Compound-3:

A solution of (D)-(−)-pantolactone (25.0 g, 192.30 mmol), β-alaninetert-butyl ester HCl (25.0 g, 137.66 mmol) and Et₃N (22.0 mL, 168.0mmol) in dioxane (250 mL) was heated at 65° C. for 3 days. The reactionmixture was cooled to RT, filtered the salt, filtrate was evaporated invacuo and purified by column chromatography to afford compound 3 (32.0g, 116.0 mmol) as light yellow syrup. Rf: 0.3 (80% EtOAc/Hexane); LCMS(M+H): 276.2; Yield: 84.5%.

Synthesis of Compound-5:

To a stirred solution of eicosapentaenoic acid (40.0 g, 132.45 mmol) andDIPEA (20 mL, 108.5 mmol) in THF (250 mL) was added CDI (21.5 g, 132.45mmol) in portions at below 10° C. over a period of 15 min. Afterstirring for 1 h at RT, was added compound 3 (36.0 G, 130.9 mmol) in THF(200 mL) and cat amount of DMAP and resulting mixture was stirred at RTfor 3 days. The solvent was evaporated in vacuo and the crude materialwas subjected to column chromatography (30-50% EtOAc/Hexanes, Rf: 0.4)to afford compound 5 (27.0 g, 48.3 mmol) as yellow oil. LCMS (M+H):560.8; Yield: 36.5%.

Synthesis of Compound-7:

To a solution of compound 5 (25.0 g, 44.6 mmol) and DIPEA (19.4 mL,111.6 mmol) in CH₂Cl₂ (300 mL), was added nicotnoyl chloridehydrochloride (9.5 g, 53.6 mmol), compound 6 in portions at below 10° C.over 10 min and the reaction mixture was stirred for 24 h. One moreportion of nicotinoyl chloride hydrochloride (9.5 g, 53.6 mmol) andDIEPA (19.4 mL, 111.6 mmol) were added and the reaction was continuedfor 24 h. The crude reaction mixture was washed with water (300 mL) andthe organic layer was dried, filtered and evaporated to give crude oil,which was subjected to column chromatography (40-70% EtOAc/hexanes,Rf=0.5) to afford Compound 8 (13.2 g, 19.8 mmol) as yellow syrup. Yield:44.5%; LCMS (M+H): 665.7.

Synthesis of Compound-8:

To a stirred solution of compound 7 (13.0 g, 19.5 mmol) in CH₂Cl₂ (150mL) was added trifluoroacetic acid (7 mL) at RT and the mixture wasstirred at RT for 24 h. The solvent was evaporated and the residue wasdissolved in EtOAc (200 mL), pH was adjusted to 5-5.5 with aq. NaHCO₃solution. The organic layer was separated, dried over Mg₂SO₄, filteredand evaporated in vacuo. The residue was purified by columnchromatography (60-100% EtOAc/Hexane, Rf: 0.1) to afford compound 8 (3.5g, 5.59 mmol) as yellow oil. Yield: 28.5%; LCMS (M+H): 609.7.

Preparation of amino(3,3-dimethylguanidino)methaniminium3-((R)-4-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyloxy)-3,3-dimethyl-2-(nicotinoyloxy)butanamido)propanoate

A Solution of compound 8 (2.0 g) and metformin free base (0.43 g) inEtOAc (25 mL) was stirred at RT for 2 h and evaporated the solvent invacuo. The residue was taken in ether (60 mL) and stirred at RT for 2 h.The solid residue was filtered, washed with ether (3×20 mL) and wasdried to afford yellow solid (1.8 g, 2.4 mmol), Yield: 74.0%. MolecularFormula: C₃₉H₅₉N₇O₇; Molecular Wt: 737.92.

Example-3

Synthesis of Compound-3:

A solution of (D)-(−)-pantolactone (25.0 g, 192.30 mmol), β-alaninetert-butyl ester HCl (25.0 g, 137.66 mmol) and Et₃N (22.0 mL, 168.0mmol) in dioxane (250 mL) was heated at 65° C. for 3 days. The reactionmixture was cooled to RT, filtered the salt, filtrate was evaporated invacuo and purified by column chromatography to afford compound 3 (32.0g, 116.0 mmol) as light yellow syrup. Rf: 0.3 (80% EtOAc/Hexane); LCMS(M+H): 276.2; Yield: 84.5%.

Synthesis of Compound-5:

To a stirred solution of eicosapentaenoic acid (40.0 g, 132.45 mmol) andDIPEA (20 mL, 108.5 mmol) in THF (250 mL) was added CDI (21.5 g, 132.45mmol) in portions at below 10° C. over a period of 15 min. Afterstirring for 1 h at RT, was added compound 3 (36.0 G, 130.9 mmol) in THF(200 mL) and cat amount of DMAP and resulting mixture was stirred at RTfor 3 days. The solvent was evaporated in vacuo and the crude materialwas subjected to column chromatography (30-50% EtOAc/Hexanes, Rf: 0.4)to afford compound 5 (27.0 g, 48.3 mmol) as yellow oil. LCMS (M+H):560.8; Yield: 36.5%.

Synthesis of 2-(chlorocarbonyl)phenyl 2-(acetyloxy)benzoate, Compound-6

To a solution of salsalicylic acid (salsalate) (5.0 g, 19.37 mmol) inacetic anhydride (15.0 mL, 147.0 mmol) was added 3 drops of conc. H₂SO₄and the mixture was stirred at RT for 16-20 h. The mixture was dilutedwith ice cold water (50 mL) and precipitated solid was filtered, washedwith water (2×10 mL), hexanes (20 mL) and dried to afford2-{[2-(acetyloxy)benzoyl]oxy}benzoic acid, 11 (5.5 g, mmol) as whitesolid. Rf: 0.3 (50% EtOAc/hexanes).

The above obtained acid was taken in CH₂Cl₂ (50 mL), 3 drops of DMF wasadded. To the suspension oxallyl chloride (1.8 mL, 20.0 mmol) was addeddrop wise and the mixture was stirred for 4 h (clear solution obtained).The solvent was evaporated in vacuo and the crude material was used assuch for further steps.

Synthesis of Compound-7:

To a solution of compound 5 (8.0 G, 15.9 mmol) and DIPEA (5.2 mL, 30.0mmol) in CH₂Cl₂ (100 mL) was added compound 6 (5.5 G, 17.3 mmol) inCH₂Cl₂ (50 mL) drop wise and the resulting mixture was stirred for 24 h.The reaction mixture was diluted with water (100 mL) and organic layerwas separated, dried and evaporated in vacuo. The crude material waspurified by flash chromatography (20-30% EtOAc/hexanes) to affordcompound 7 (1.8 g, 21.3 mmol) as light yellow syrup. Yield: 13.4%, Rf:0.5 (40% EtOAc/hexanes).

Synthesis of Compound-8:

A solution of compound 7 (1.6 g, 1.9 mmol) in Toluene (20 mL) was mixedwith Silica-gel (10.0 g) and heated at 100° C. for 2 h. The crudemixture was purified by flash chromatography (30-60% EtOAc/hexanes) toafford compound 8 (1.1 g, 1.4 mmol)) as gummy syrup. Yield: 74.0%, Rf:0.3 (70% EtOAc/hexanes).

Preparation ofamino(3,3-dimethylguanidino)methaniminium3-((R)-2-((2-((2-acetoxybenzoyl)oxy)benzoyl)oxy)-4-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyloxy)-3,3-dimethylbutanamido)propanoate

Compound 8 (1.0 g, mmol) and metformin free base (0.17 g, mmol) in ether(20 mL) was stirred for 3 h and filtered the gel type solid wasobtained, the solid was washed with ether (2×10 mL) and dried to affordyellow semi-solid. Molecular Formula: C49H66N6O11; M. Wt: 915.08.

Example-4

The Solubility of the Compound of Example-1, Example-2, Example-3 inWater was Compared with that of Eicosapentaenoic Acid (EPA):

Measurement of the water solubility of the test compound wasaccomplished by using methods well known to those skilled in the art.Specifically, to a weighed amount of the test compounds of Example-1,Example-2, Example-3 and EPA were taken in separate vials; distilledwater was added in small portions until a clear solution was obtained.The water solubility is calculated by dividing the weight of salt, inmg, by the volume of the solution, in mL. The water solubility of thecompounds of example-1, example-2, example-3 compared to EPA alone wereas follows:

EPA: <0.3 mg/mL,

Example-1: 60 mg/mL,

Example-2: 103 mg/mL,

Example-3: 98 mg/mL.

Example-5 Rat Pharmacokinetics of Example-1 compound,amino(3,3-dimethylguanidino)methaniminium3-((R)-2-hydroxy-4-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyloxy)-3,3-dimethylbutanamido)propanoate

Single dose oral pharmacokinetic (PK) parameters for example-1 weredetermined in Sprague-Dawley rats. Example-1 compound was administeredby oral gavage as an aqueous solution to 12 rats, 6 males and 6 females.Rats were dosed at 245 mg/kg of example-1 compound. Blood samples wereobtained by jugular vein catheter. Samples were collected at 0.25, 0.5,1, 2, 4, 8, 12, and 24 hrs post dose and the resulting plasma sampleswere analyzed for metformin and EPA. Calculated PK parameters shownbelow in table-1 are mean values from 12 rats.

TABLE 1 Analyte EPA Metformin Cmax (μg/mL)  16.12 2.867 Tmax (hrs)  0.781.12  AUC (0-24) (μg*h/mL) 319.34 9.21 

EQUIVALENTS

The present disclosure provides among other things compositions andmethods for treating diabetes and pre-diabetes and their complications.While specific embodiments of the subject disclosure have beendiscussed, the above specification is illustrative and not restrictive.Many variations of the systems and methods herein will become apparentto those skilled in the art upon review of this specification. The fullscope of the claimed systems and methods should be determined byreference to the claims, along with their full scope of equivalents, andthe specification, along with such variations.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted above, are hereby incorporated by reference in their entirety asif each individual publication or patent was specifically andindividually indicated to be incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

The invention claimed is:
 1. A composition comprising Formula I,

which is at least one of: a salt of biguanide with any one of apolyunsaturated fatty acid molecular conjugate and a derivative of thepolyunsaturated fatty acid molecular conjugate, and a mixture ofbiguanide in a pharmaceutically acceptable salt form, any one of an acidof the polyunsaturated fatty acid molecular conjugate and an acid of thederivative of the polyunsaturated fatty acid molecular conjugate, and apharmaceutically acceptable substance, wherein the pharmaceuticallyacceptable substance is at least one of a solvate, a polymorph, anenantiomer, a stereoisomer and a hydrate thereof, wherein R¹, R², R³, R⁴are independently selected from the group consisting of H, D, CD₃ andCH₃, and wherein RH represents at least one of the polyunsaturated fattyacid molecular conjugate, the acid of the polyunsaturated fatty acidmolecular conjugate, the derivative of the polyunsaturated fatty acidmolecular conjugate, and the acid of the derivative of thepolyunsaturated fatty acid molecular conjugate, and is independentlyselected from the group consisting of:  a molecular conjugate ofeicosapentaenoic acid, D-pantothenic acid and salsalate;  a molecularconjugate of eicosapentaenoic acid, D-pantothenic acid and2-((2-acetoxybenzoyl)oxy)benzoic acid;  a molecular conjugate ofeicosapentaenoic acid, D-pantothenic acid and nicotinic acid;  amolecular conjugate of eicosapentaenoic acid, D-pantothenic acid andhydroxytyrosol;  a molecular conjugate of eicosapentaenoic acid,D-pantothenic acid and R-lipoic acid;  a molecular conjugate ofeicosapentaenoic acid and fumaric acid; and  a molecular conjugate ofeicosapentaenoic acid, D-pantothenic acid.
 2. A pharmaceutical compoundcomprising amino(3,3-dimethylguanidino)methaniminium3-((R)-2-hydroxy-4-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyloxy)-3,3-dimethylbutanamido)propanoateand pharmaceutically acceptable carrier